Our laboratory has demonstrated that several chemical carcinogens, including the colon carcinogens n-methyl-n-nitro-n-nitrosoguaniine (MNNG) and 1,2 dimethylhydrazine dihydrochloride (DMH) are agonists of guanylate cyclase (GC) in human and/or rat colonic epithelium. Soluble GC and cyclic GMP (cGMP), but not cyclic AMP (cAMP), are increased within minutes after exposure of colonic epithelium to MNNG. These acute responses could represent primary events in the process by which MNNG and other carcinogens initiate malignant conversion. The rapid increase in cellular cGMP/cAMP molar ratio induced by MNNG is a change similar in direction to that found in human adenocarcinomas, and may favor unregulated cell growth. Based on these findings we propose to study: (1) cGMP and cAMP metabolism during normal growth and differentiation of colonic epithelium, by comparing steady-state cyclic nucleotide levels and the enzymes regulating cAMP and cGMP metabolism in superifical (non-proliferating) and deep (proliferating) layers of rat and human colonic epithelium; (2) the in vitro effects of the colon carcinogens MNNG, DMH, methylazoxymethanol (MAM) acetate, 3,2'dimethyl 4-aminobiphenyl, and of recognized reactive metabolites of these carcinogens on cyclic nucleotide metabolism in superficial and deep layers of colonic epiihelium; (3) the acute changes in cyclic nucleotide metabolism which occur in vivo in colonic epithelium after a single large pulse dose of MNNG, DMH or MAM acetate and the correlation of any observed changes with DNA synthetic activity; (4) the mechanism by which MNNG and DMH activate the soluble guanylate cyclase of colonic epithelium, by examining the action of these agents on the purified enzyme derived from this tissue; (5) cGMP-dependent protein kinase activity in normal colonic epithelium, the ability of this enzyme system to phosphorylate colonic epithelial membrane fractions and nuclei and responses to MNNG and other carcinognes; (6) cAMP and cGMP metabolism and cyclic nucleotide-dependent protein kinase activities in human adenocarcinomas compared to the same parameters in the uninvolved epithelium from patients undergoing therapeutic colonic resection for tumors or diverticular disease.